This invention relates to a mild, efficient, stereo-selective method for the one step conversion of primary and secondary alcohols to their corresponding thiol ester and thiol derivatives with inversion of configuration: ##STR2## wherein ROH is the alcohol taken in reaction and wherein R'COSH is the thiolacid reagent of choice. The transformation of the resulting thiol ester 6 to the corresponding thiol 7 is achieved by saponification or by reductive methods. The process of the present invention permits the above transformation upon alcohols which heretofore would have been considered too labile to undergo conventional transformation to the corresponding thiol analogue. Alcoholic substrates 4 of primary interest are indicated below as are their corresponding thiol ester and thiols.
All prior methods for the conversion of an alcohol to a thiol ester or thiol consist of a series of chemical reactions. The alcohols are first converted to an activated species (halide or tosylate, for example) and then displaced with a suitable sulfur containing nucleophile. These transformations are often not applicable to sensitive molecules, such as beta-lactams, due to the harshness of reaction conditions typically employed and the accompanying by-products produced.
The process of the present invention, however, differs from known methodology as the alcoholic substrates are converted directly to the thiol ester derivatives in one step under very mild reaction conditions. Thus alcohols containing other sensitive functionality (such as the beta-lactan) can be successfully transformed to their corresponding thiol derivatives in high yield. The process of the present invention is also more efficient and of higher stereoselectivity than prior methods. The recited advantages of the process of the present invention are in part attributable to the use of the triphenylphosphine-diisopropyl azodicarboxylate mediated hydroxyl activation with subsequent thiol acid displacement.
A class of alcoholic substrates which are converted to their corresponding thiol ester and thiol forms by the process of the present invention include thienamycin intermediates, described below, which are useful, for example, in preparing the known thiol and thiol ester analogues of thienamycin: ##STR3## wherein R' is loweralkyl having 1-6 carbon atoms.
Still in the area of nonclassical beta-lactam carbapenem antibiotics such as thienamycin, it should be noted that the transformation made available by the process of the present invention is preferably applied to intermediates in the synthesis of such final carbapenem products. Thus, for example, in the preparation of thienamycin the intermediate azetidinones which bear the hydroxyethyl substituent may be converted to the thiol or thiol ester for subsequent elaboration to desired species such as those shown above. The following azetidinones are representative of such alcoholic substrates that may be employed in this process. Such azetidinones are disclosed in the following publications which are incorporated herein by reference D. G. Melillo, I. Shinkai, T. Liu, K. Ryan, M. Sletzinger, Tet. Lett. 2783, 1980; T. N. Salzmann, R. W. Ratcliffe, F. A. Bouffard, and B. G. Christensen, J. Am. Chem. Soc. 102, 6161, 1980.: ##STR4## wherein R.degree.' is hydrogen and as previously defined; R.degree.' is: ##STR5##
Other alcohols ROH which may be transformed to their corresponding thiol and thiol esters are demonstrated in the following table:
______________________________________ Compound ROH RSH ______________________________________ 1. 2(-)octanol 2(+)octane thiol 2. 3-.beta.-cholesterol 3.alpha.-cholesteryl thiol 3. benzyl alcohol benzyl- mercaptan 4. cinamyl alcohol cinamyl thiol ______________________________________
The process of the present invention can also be used for the synthesis of various mercapto analogues of prostaglandins and thromboxanes, for example, 15 epi PGA.sub.2 methylester can be converted to the 15-thioacetyl PGA.sub.2 methyl ester. Selective hydrolysis to the 15 mercapto--PGA.sub.2 methyl ester of similar utility is accomplished by hydrolysis with methanolic HCl or sodium methoxide in methanol. ##STR6##